Chasing Down The Source

A global epidemic of diabetes might be averted if we could rid ourselves of a passion for Twinkies and television remotes.

Fat chance, say scientists searching for a cure for the complex and misunderstood disease.

"Diet is always the first therapy prescribed and it almost never works, except in very, very motivated individuals," says Dr. Markus Stoffel, director of the laboratory of metabolic diseases at Rockefeller University in New York.

So Stoffel and other diabetes researchers are exploring the dimly lit intersection where genes and behavior conspire to create diabetes. They hope to discover the source of a disease that can afflict people of all ages - and pants sizes.

In most cases, losing weight seems to delay or even prevent the onset of Type 2 diabetes, the most common form of the disease. Yet a health club membership and more helpings of Brussels sprouts do nothing for Type 1 diabetics and may have only limited benefits for diabetics already diagnosed with Type 2.

"Diabetes is much more complicated than we ever imagined," Stoffel says.

The last quarter-century of research has clearly demonstrated how poor diet and sedentary lifestyles make it harder for the body to efficiently use insulin, the essential hormone that orchestrates the body's use of blood sugars, the primary fuel used by our cells.

Now the emphasis in research is shifting to finding ways to restore the body's ability to secrete insulin - a deficiency that may have little to do with diet or lifestyle.

That goal is crucial to survival for the 5 percent to 10 percent of diabetics with Type 1 diabetes, also known as juvenile diabetes, in which the patient's own immune system attacks insulin-producing cells in the pancreas.

And Type 2 diabetics - even those who exercise and eat wisely - still tend to show a steady decline in their ability to secrete insulin, recent research in Great Britain has found.

New Approaches

To fix that problem, some companies are taking a mechanical approach. They're developing implantable insulin pumps that are linked with glucose sensors, in an attempt to artificially mimic the patient's blood sugar regulatory system, says Dr. William Petit Jr., medical director of the Joslin Diabetes Center affiliate at New Britain General Hospital.

Meanwhile, other researchers are trying to get the patient's own body to do that work with cell therapies. The idea is to replenish the insulin-producing beta cells made in areas of the pancreas known as the islets of Langerhans.

"There's absolutely a major emphasis on beta cell research. It's involved in both Type 1 and Type 2 and has the potential to form the basis of therapies for both forms of diabetes," says Dr. Judith Fradkin, director of the diabetes division of the National Institute of Diabetes and Digestive and Kidney Diseases.

Pancreas transplants have been a boon for Type 1 diabetics. But there are about 800,000 patients with Type 1 diabetes and only about 3,000 pancreases available each year.

The answer to the shortfall, many researchers believe, lies in stem cell research.

Susan Bonner-Weir and colleagues at the Joslin Diabetes Center in Boston managed to coax cells from the duct of the pancreas into becoming insulin-producing cells. She is investigating whether these cells are adult stem cells that can be replicated and used for transplants.

"If we grow those in culture, maybe we will be able to grow new islets," Bonner-Weir says. "The potential is so tantalizing."

While advances in the field of stem cell biology have come at increasing speed in the last two years, more money needs to be spent on such research, including on human embryonic stem cell lines that are reproduced easily in the laboratory and can grow into any tissue, she says.

"The question is how fast can we get there," Bonner-Weir says. "We need to pour more money into research. We need more people working on it. With some good luck, it could all break open in a month. Or it might be 10 years."

Scientists also are still searching for root causes of diabetes. They are perplexed by the link between diabetes and obesity: Most diabetics are overweight, yet most overweight people aren't diabetic.

A South Pacific Island

That's why on the Micronesian island of Kosrae scientists from Rockefeller University are exploring the genetics of diabetes.

The Kosraens, like the Pima Indians in Arizona, apparently never had diabetes before the introduction of a Western diet and more sedentary lifestyle. Today, about half of adult Kosraens and Pima Indians develop diabetes, some of the highest rates in the world.

One reason, scientists such as Stoffel believe, lies in the "thrifty gene" hypothesis. Under the theory, the ability to quickly store food as fat may have helped individuals survive famines. So a number of fat-storing gene variations would have evolved in populations that faced many periods of starvation over history.

The ability to store fat, once a genetic blessing in times of want, has become a curse in times of plenty.

Perhaps, Stoffel says, the ancestors of the Pimas and Kosraens faced many famines, while Caucasian populations faced fewer such episodes.

By tracing the genetic roots of people of the island, researchers hope to identify those gene variations, called alleles, that may play a protective role or, conversely, help trigger the disease, Stoffel says.

"Our hypothesis is higher risk is associated with Micronesian alleles, and that the Caucasian alleles will be protective," he says.

But why aren't most overweight people diabetic?

The answer is most people manage to adjust levels of insulin they secrete to compensate for insulin resistance, says Dr. Nicolas N. Abourizk, section chief of endocrinology at St. Francis Hospital and Medical Center.

Some people appeared to be doubly cursed. Not only are they predisposed to weight gain and insulin resistance, they appear unable to adjust insulin secretion to compensate, he says.

The ultimate goal in this study is to develop drugs that interfere with the damaging end products of bad genes or mimic the actions of protective genes.